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      MICU1 and MICU2 Finely Tune the Mitochondrial Ca 2+ Uniporter by Exerting Opposite Effects on MCU Activity

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          Summary

          Mitochondrial calcium accumulation was recently shown to depend on a complex composed of an inner-membrane channel (MCU and MCUb) and regulatory subunits (MICU1, MCUR1, and EMRE). A fundamental property of MCU is low activity at resting cytosolic Ca 2+ concentrations, preventing deleterious Ca 2+ cycling and organelle overload. Here we demonstrate that these properties are ensured by a regulatory heterodimer composed of two proteins with opposite effects, MICU1 and MICU2, which, both in purified lipid bilayers and in intact cells, stimulate and inhibit MCU activity, respectively. Both MICU1 and MICU2 are regulated by calcium through their EF-hand domains, thus accounting for the sigmoidal response of MCU to [Ca 2+] in situ and allowing tight physiological control. At low [Ca 2+], the dominant effect of MICU2 largely shuts down MCU activity; at higher [Ca 2+], the stimulatory effect of MICU1 allows the prompt response of mitochondria to Ca 2+ signals generated in the cytoplasm.

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          Highlights

          • MICU1 and MICU2 form an obligate heterodimer

          • MICU1 enhances MCU opening

          • MICU2 acts as an MCU gatekeeper

          Abstract

          Mitochondrial calcium uptake is rapid in response to calcium signaling. Patron et al. demonstrate that this response is not intrinsic to the mitochondrial calcium uniporter (MCU) but rather is dependent on a disulfide-mediated dimer of MCU interactors (MICU1 and MICU2). At low [Ca 2+], MICU2 shuts down MCU activity, but after Ca 2+ stimulation, MICU2 inhibition is released and MICU1 enhances MCU opening.

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          Most cited references15

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          Mitochondria as sensors and regulators of calcium signalling.

          During the past two decades calcium (Ca(2+)) accumulation in energized mitochondria has emerged as a biological process of utmost physiological relevance. Mitochondrial Ca(2+) uptake was shown to control intracellular Ca(2+) signalling, cell metabolism, cell survival and other cell-type specific functions by buffering cytosolic Ca(2+) levels and regulating mitochondrial effectors. Recently, the identity of mitochondrial Ca(2+) transporters has been revealed, opening new perspectives for investigation and molecular intervention.
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            MICU1 encodes a mitochondrial EF hand protein required for Ca2+ uptake

            Mitochondrial calcium uptake plays a central role in cell physiology by stimulating ATP production, shaping cytosolic calcium transients, and regulating cell death. The biophysical properties of mitochondrial calcium uptake have been studied in detail, but the underlying proteins remain elusive. Here, we utilize an integrative strategy to predict human genes involved in mitochondrial calcium entry based on clues from comparative physiology, evolutionary genomics, and organelle proteomics. RNA interference against 13 top candidates highlighted one gene that we now call mitochondrial calcium uptake 1 (MICU1). Silencing MICU1 does not disrupt mitochondrial respiration or membrane potential but abolishes mitochondrial calcium entry in intact and permeabilized cells, and attenuates the metabolic coupling between cytosolic calcium transients and activation of matrix dehydrogenases. MICU1 is associated with the organelle’s inner membrane and has two canonical EF hands that are essential for its activity, suggesting a role in calcium sensing. MICU1 represents the founding member of a set of proteins required for high capacity mitochondrial calcium entry. Its discovery may lead to the complete molecular characterization of mitochondrial calcium uptake pathways, and offers genetic strategies for understanding their contribution to normal physiology and disease.
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              Regulation of mitochondrial dehydrogenases by calcium ions.

              Studies in Bristol in the 1960s and 1970s, led to the recognition that four mitochondrial dehydrogenases are activated by calcium ions. These are FAD-glycerol phosphate dehydrogenase, pyruvate dehydrogenase, NAD-isocitrate dehydrogenase and oxoglutarate dehydrogenase. FAD-glycerol phosphate dehydrogenase is located on the outer surface of the inner mitochondrial membrane and is influenced by changes in cytoplasmic calcium ion concentration. The other three enzymes are located within mitochondria and are regulated by changes in mitochondrial matrix calcium ion concentration. These and subsequent studies on purified enzymes, mitochondria and intact cell preparations have led to the widely accepted view that the activation of these enzymes is important in the stimulation of the respiratory chain and hence ATP supply under conditions of increased ATP demand in many stimulated mammalian cells. The effects of calcium ions on FAD-isocitrate dehydrogenase involve binding to an EF-hand binding motif within this enzyme but the binding sites involved in the effects of calcium ions on the three intramitochondrial dehydrogenases remain to be fully established. It is also emphasised in this article that these three dehydrogenases appear only to be regulated by calcium ions in vertebrates and that this raises some interesting and potentially important developmental issues.
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                Author and article information

                Contributors
                Journal
                Mol Cell
                Mol. Cell
                Molecular Cell
                Cell Press
                1097-2765
                1097-4164
                06 March 2014
                06 March 2014
                : 53
                : 5
                : 726-737
                Affiliations
                [1 ]Department of Biomedical Sciences, University of Padova, Via Ugo Bassi 58, 35131 Padova, Italy
                [2 ]CNR Neuroscience Institute, Via Ugo Bassi 58, 35131 Padova, Italy
                [3 ]Department of Biology, University of Padova, Via Ugo Bassi 58, 35131 Padova, Italy
                Author notes
                []Corresponding author diego.destefani@ 123456gmail.com
                [∗∗ ]Corresponding author rosario.rizzuto@ 123456unipd.it
                Article
                S1097-2765(14)00074-4
                10.1016/j.molcel.2014.01.013
                3988891
                24560927
                2e96196c-2ad9-40fc-ad55-7c92e18eaa24
                © 2014 Elsevier Inc. All rights reserved.
                History
                : 5 November 2013
                : 18 December 2013
                : 16 January 2014
                Categories
                Article

                Molecular biology
                Molecular biology

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